Apoptosis, or programmed cell death, plays an important role ensuring a proper balance between cell proliferation and cell loss in multicellular organisms. Disruption of this pathway is implicated in many human diseases, including cancer (Reed, J. C., Cell Death and Differentiation, 13:1379-1386 (2006)). Targeting critical apoptosis regulators is an attractive approach for the development of anticancer therapeutics and therapies for other human diseases caused by biologically impaired apoptosis.
Proteins belonging to the Bcl-2 (B-cell lymphocyte/leukemia-2) family play a central role in regulating apoptosis (Chan, S.-L. et al., Clin. and Exper. Pharmacol. and Physiol., 31:119-128 (2004)). This family contains proteins promoting cell survival (Bcl-2, Bcl-b, Bcl-Xl, Bcl-w, Mcl-1, A1) and proteins promoting cell death (i.e., Bak, Bax, Bim, Bid, etc). Family members share up to four Bcl-2 homology (BH) domains and formation of homo- or heterodimers via these BH domains modulates each other's function(s) as cell death agonists or antagonists. Cellular ratios between proapoptotic and prosurvival family members dictate cellular fate. For example, prosurvival Bcl-2 family protein levels are elevated in many cancers enabling tumor cells more resistant to apoptosis. Consequently, antagonizing prosurvival Bcl-2 family protein function in tumor cells is a promising strategy for the development of anticancer therapeutics. Conceptually this therapeutic strategy is also applicable towards other diseases brought about by the disrupted cellular balance of proapoptotic and prosurvival Bcl-2 family proteins.
There remains a need for compounds that are useful as Bcl-2 family prosurvival protein antagonists.
Applicants have found potent compounds that have activity as small molecule Bcl-2 family prosurvival protein antagonists for cancer treatment and other diseases caused by impaired apoptosis. These compounds are provided to be useful as pharmaceuticals with desired stability, bioavailability, therapeutic index, and toxicity values that are important to their drugability.